Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug. Increasing the bioavailability of low-solubility drugs has been the subject of much research. Increasing bioavailability depends on improving the concentration of dissolved drug in solution to improve absorption.
It is well known that the amorphous form of a low-solubility drug that is capable of existing in either the crystalline or amorphous form may temporarily provide a greater aqueous concentration of drug relative to the equilibrium concentration obtained by dissolution of the drug in a use environment. Such amorphous forms may consist of the amorphous drug alone, a dispersion of the drug in a matrix material, or the drug adsorbed onto a substrate. It is believed that such amorphous forms of the drug may dissolve more rapidly than the crystalline form, often dissolving faster than the drug can precipitate from solution. As a result, the amorphous form may temporarily provide a greater-than equilibrium concentration of drug.
While such amorphous forms may show initially enhanced concentration of the drug in a use environment, nevertheless the improved concentration is often short-lived. Typically, the initially enhanced drug concentration is only temporary and quickly returns to the lower equilibrium concentration.
One problem with using the amorphous form of a drug is that the solid drug may not be stable physically in the amorphous form. Often the crystalline form of the drug has a lower free energy, and thus over time, the amorphous drug will tend to crystallize. The rate of crystallization may be influenced by storage conditions, such as temperature and humidity, as well as the constituents of the composition.
Babcock, et al. in commonly assigned U.S. patent application Ser. No. 10/173,987 published as US 2003/0054037, incorporated herein by reference, disclose a solid adsorbate comprising a low-solubility drug adsorbed onto a substrate, the substrate having a surface area of at least 20 m2/g, wherein at least a major portion of the drug in the adsorbate is amorphous. The composition provides enhanced drug concentrations when administered to an aqueous environment of use. In another embodiment, the composition comprises a solid adsorbate of a low-solubility drug adsorbed onto a substrate mixed with a concentration-enhancing polymer. In yet another embodiment, the composition comprises a solid adsorbate and a concentration-enhancing polymer adsorbed onto a substrate.
Babcock, et al. disclose that the adsorbate may be mixed with surfactants or surface-active agents to increase the rate of dissolution by facilitating wetting, formation of micelles, or inhibiting crystallization or precipitation of the drug. Such materials can comprise up to 5 wt % of the composition.
Takeuchi, Chem. Pharm. Bull. 35(9) 3800-3806 (1987), discloses spray dried compositions of the drug tolbutamide and very fine hydrophilic silica particles, Aerosil® 200. A 1:1 weight solution of tolbutamide and Aerosil® 200 was sprayed from a solution of 2% ammonia water. The authors indicate that at least some of the drug was amorphous.
Reuter et al., U.S. Pat. No. 4,835,186 discloses a spray dried suspension of colloidal silica in a lower alkanol solution of ibuprofen and cellulose acetate phthalate. The examples disclose spray dried compositions comprising ibuprofen, CAP, colloidal silica and a small amount of castor oil, spray dried from a solution of ethyl acetate and isopropyl alcohol.
WO 01/00180A1 discloses a self-emulsifying drug (SED) composition comprising a o-(chloroacetylcarbamoyl)fumigillol, a pharmaceutically acceptable carrier comprising an oily constituent and at least one surfactant, and a stabilizing component, the stabilizing component comprising water, an acid, and an adsorbent core complex forming agent. The pharmaceutically acceptable carrier having the drug can be filled, mixed, adsorbed, filtered, or otherwise combined with the adsorbent or complex forming agent. Exemplary adsorbents include active charcoal and silica gel.
Monkhouse et al. (J. Pharm. Sci., Vol. 61, No. 9, 1972), disclose forming adsorbents by mixing a drug and water insoluble adsorbent such as fumed silicon dioxide or precipitated silicic acid, adding a sufficient quantity of an organic solvent to dissolve the drug, and then evaporating the solvent by a stream of filtered air.
Yamamoto et al., “Adsorption of Pharmaceutical Organic Compounds onto Porous Materials,” (in Surfaces of Nanoparticles and Porous Materals, Scwarz and Contescu eds, 1999) reviews among other things, improving dissolution of drugs by using porous materials to form drug that is the amorphous state.
Nevertheless, what is still desired is a composition that may enhance the dissolution and/or bioavailability of poorly soluble drugs. These needs and others that will become apparent to one of ordinary skill are met by the present invention, which is summarized and described in detail below.